Assistant John Stevens will become head coach, and assistant general manager Paul Holmgren will be the interim general manager, trying to become the latest combination to end their 31-year Stanley Cup drought.
The Flyers are 1-6-1 and have the fewest points in the NHL.
"The decisions that had to be made, I was letting other people make them," said Clarke, acknowledging he was burned out. "I deeply regret not being able to bring a Stanley Cup here. ... I didn't deliver."
Flyers chairman Ed Snider said he began evaluating the team after an embarrassing 9-1 loss to Buffalo last week and decided change was necessary.
"Over the last several weeks it has become clear that it was time to make a change," Snider said in a statement. "This is not easy for anyone involved, but we have to do what is best for this team."
Clarke said the Flyers' record played no role in his resignation. He said he began feeling spent during last year's draft and hoped for new energy once the season started. That never happened.
"I just don't have the desire to do what this job requires," Clarke said. "I was tired of doing it."
Stevens will be behind the bench when the Flyers play at home Thursday against Atlanta.
As general manager, Clarke never matched the success he had as a Hall of Fame player when he led the Flyers to Stanley Cup championships in the 1973-74 and 1974-75 seasons. Clarke was in his 13th season in his second stint as general manager, after handling the GM role in the 1980s.
"Bob Clarke has been the heart and soul of the Flyers for nearly 40 years," Snider said. "Bob was the driving force behind our Stanley Cups as a player, and as president and general manager, he built the Flyers into one of the premier franchises in hockey. I will always think of Bob as the 'Ultimate Flyer' and there is always a position within our organization for Bob Clarke."
Hitchcock signed a three-year contract though the 2008-09 season in training camp and was in his fourth season with the Flyers. He led the Flyers to the conference final in 2004, where they lost to the Tampa Bay Lightning, who later won the Stanley Cup.
Before Hitchcock was hired, the Flyers used five coaches in the previous six seasons.
"He realized that we had to make a change, and he's behind the organization and he's willing to do whatever he can to help the organization move forward," Snider said.
Hitchcock did not immediately return a phone message left by The Associated Press.
In 10 NHL seasons with Dallas and Philadelphia, Hitchcock is 408-249-100. He is 66-51 in playoff games and won the Stanley Cup with Dallas in 1999.
Stevens, 40, was the head coach of the Flyers' American Hockey League affiliate, the Philadelphia Phantoms, for the past six seasons, leading the team to the Calder Cup in 2005.
Stevens was Philadelphia's third-round pick by the Flyers in 1984 and played 53 career games with the Flyers and Hartford Whalers.
"John Stevens has quickly proven that he can coach in the National Hockey League," Snider said. "He worked very closely with many of our younger players when he coached them as Phantoms. We believe that we have a core of great young talent and we think that John is the right guy to coach this team."
This is Philadelphia's worst start since the 1989-90 season. The Flyers have scored only 15 goals in eight games, and five of them are from Simon Gagne. In losing Friday at Florida they played without captain Peter Forsberg, who has a sprained wrist.
They are a woeful 4-for-55 on power-play chances this season.
Philadelphia was bounced in the first round of the playoffs by Buffalo last season, and has seemed ill-equipped to win a Stanley Cup. Many of the same problems they had last season have lingered, notably a plodding defence that has yet to score a goal.
The Flyers waived three players last week after the blowout loss to the Sabres, including Nolan Baumgartner, their lone free-agent signing to bolster the defence.
With a shaky defence and little offensive punch, the goaltenders have struggled, especially opening night starter Robert Esche. Esche has allowed 13 goals in two winless starts.
Clarke played for the Flyers from 1969-84, 358 goals and 1210 points, and captained the famed "Broad Street Bullies" teams in the 1970s.
Clarke immediately went from playing into management, holding the GM role from 1984-90. He returned to the position in 1994, famously feuding with Eric Lindros in the late 1990s.
"I don't know what happened. I don't know why it happened," Clarke said. "I would have never thought I'd get tired or burnt out or something. But this is what's happened. I've got to try and figure out why and how."
Hitchcock also led Dallas to two Stanley Cup finals appearances - winning the title in 1999 and going back the next year - and five straight division titles.